Sclerosing skin disorders in association with multiple sclerosis. Coincidence, underlying autoimmune pathology or interferon induced?

OBJECTIVES: To describe and analyse the manifestation of sclerosing skin disorders in patients with multiple sclerosis (MS). CASE REPORTS: We describe three patients with relapsing-remitting MS who developed skin sclerosis while receiving interferon (IFN)-beta treatment and review nine further cases of systemic sclerosis (SSc) in MS from the literature. Of all 12 patients reported, eight had limited cutaneous SSc, three had diffuse cutaneous SSc and one patient had an antisynthetase syndrome. Localised scleroderma such as morphoea was not described. The mean age at diagnosis was 25.2 years for MS (range 12 to 51) and 38.3 years for SSc (range 16 to 66). Eleven patients developed SSc after the onset of MS and manifested with skin sclerosis after a mean of 14.9 years (range 1 to 45). In five patients IFN-beta was commenced before the development of skin sclerosis (mean 4.6 years, range 1 to 8 years). There was no relationship between the onset of skin sclerosis and MS activity. With the exception of one individual, all patients had antinuclear antibodies. CONCLUSIONS: Sclerosing skin disorders may develop in the course of MS. The relatively early age of SSc onset in patients with MS suggests a genetic predisposition and/or an IFN-associated trigger.

From Visual Exploration to Storytelling and Back Again.

The primary goal of visual data exploration tools is to enable the discovery of new insights. To justify and reproduce insights, the discovery process needs to be documented and communicated. A common approach to documenting and presenting findings is to capture visualizations as images or videos. Images, however, are insufficient for telling the story of a visual discovery, as they lack full provenance information and context. Videos are difficult to produce and edit, particularly due to the non-linear nature of the exploratory process. Most importantly, however, neither approach provides the opportunity to return to any point in the exploration in order to review the state of the visualization in detail or to conduct additional analyses. In this paper we present CLUE (Capture, Label, Understand, Explain), a model that tightly integrates data exploration and presentation of discoveries. Based on provenance data captured during the exploration process, users can extract key steps, add annotations, and author "Vistories", visual stories based on the history of the exploration. These Vistories can be shared for others to view, but also to retrace and extend the original analysis. We discuss how the CLUE approach can be integrated into visualization tools and provide a prototype implementation. Finally, we demonstrate the general applicability of the model in two usage scenarios: a Gapminder-inspired visualization to explore public health data and an example from molecular biology that illustrates how Vistories could be used in scientific journals. (see Figure 1 for visual abstract).

Pathfinder: Visual Analysis of Paths in Graphs.

The analysis of paths in graphs is highly relevant in many domains. Typically, path-related tasks are performed in node-link layouts. Unfortunately, graph layouts often do not scale to the size of many real world networks. Also, many networks are multivariate, i.e., contain rich attribute sets associated with the nodes and edges. These attributes are often critical in judging paths, but directly visualizing attributes in a graph layout exacerbates the scalability problem. In this paper, we present visual analysis solutions dedicated to path-related tasks in large and highly multivariate graphs. We show that by focusing on paths, we can address the scalability problem of multivariate graph visualization, equipping analysts with a powerful tool to explore large graphs. We introduce Pathfinder (Figure 1), a technique that provides visual methods to query paths, while considering various constraints. The resulting set of paths is visualized in both a ranked list and as a node-link diagram. For the paths in the list, we display rich attribute data associated with nodes and edges, and the node-link diagram provides topological context. The paths can be ranked based on topological properties, such as path length or average node degree, and scores derived from attribute data. Pathfinder is designed to scale to graphs with tens of thousands of nodes and edges by employing strategies such as incremental query results. We demonstrate Pathfinder's fitness for use in scenarios with data from a coauthor network and biological pathways.

T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis.

A subgroup of patients with atopic dermatitis are known to have normal serum total immunoglobulin E levels, undetectable specific immunoglobulin E, and negative skin prick tests towards allergens. This form of the disease has been termed nonallergic atopic dermatitis. In this study, we found that, among 1151 chronic atopic dermatitis patients, about 10% had normal serum immunoglobulin E levels with no evidence for immunoglobulin E sensitization. We investigated immunologic mechanisms of patients with "allergic" and "nonallergic" atopic dermatitis using peripheral blood and skin biopsy samples. Our data suggest that T cells are likely involved in the pathogenesis of both forms of atopic dermatitis. Skin T cells equally responded to superantigen, staphylococcal enterotoxin B, and produced interleukin-2, interleukin-5, interleukin-13, and interferon-gamma in both forms of the disease. Interleukin-4, however, was not detectable in the skin biopsies of both atopic dermatitis types and was secreted in very low amounts by T cells cultured from the skin biopsies. Moreover, skin T cells from nonallergic atopic dermatitis patients expressed lower interleukin-5 and interleukin-13 levels compared with allergic atopic dermatitis patients. Accordingly, T cells isolated from skin biopsies of atopic dermatitis, but not from the nonallergic atopic dermatitis, induced high immunoglobulin E production in cocultures with normal B cells that was mediated by interleukin-13. In addition, B cell activation with high CD23 expression was observed in the peripheral blood of atopic dermatitis, but not nonallergic atopic dermatitis patients. These data suggest, although high numbers of T cells are present in lesional skin of both types, a lack of interleukin-13-induced B cell activation and consequent immunoglobulin E production in nonallergic atopic dermatitis.

Apoptosis in HIV-infected individuals is an early marker occurring independently of high viremia.

We have analyzed the immunoreactivity of peripheral blood mononuclear cells by determining the proliferative response to four mitogens, one superantigen, and one recall antigen together with the occurrence of activation-induced apoptosis from 213 HIV-1-seropositive individuals from all stages of infection. The expected decline of immunoreactivity observed with time after infection correlated with disease progression and the loss of CD4 cells. Apoptosis was already detectable at the early stages of infection and increased only slightly with disease progression. In analyzing 13 patients with high and low apoptosis rates we observed no correlation to HIV-1 viremia. Our results argue that mitogen-induced apoptosis occurs in both infected and noninfected T cells and can be detected before mitogenic responsiveness is reduced.

Quantification of HIV-1 viral RNA and proviral DNA by isotopic competitive PCR.

A quantitative isotopic competitive PCR (icPCR) assay was established using 32P-labeled primers targeting the HIV-1 gag gene followed by quantification using a phosphoimager. The detection limit varied from 3 to 10 molecules of DNA and 10 to 100 molecules of RNA per reaction. The icPCR quantification of HIV-1 DNA copies correlated well with the cell number of 8E5/LAV cells bearing a single provirus (r2 = 0.95). Provirus quantification was applied to overnight infected donor PBMCs, thereby determining infectious virus titres in culture supernatants as a rapid alternative to limiting dilution culture. Parallel quantification of the HIV-1 RNA indicated the infectious virus fraction to be 0.3%. In 39 HIV-1-infected patients with clinical stages A (n = 17), B (n = 15), and C (n = 7), the HIV-1 RNA in the plasma was determined ranging from 100 to 90600 RNA copies/ml. The results of icPCR and a commercial assay (ROCHE Amplicor HIV-1 Monitor) correlated well (r = 0.97). In 13 additional patients, the plasma viral load per ml was compared with the proviral load per 10(6) PBMC showing a viral excess of 10-1000-fold (mean of 85, r = 0.7, P < 0.01). It is concluded that icPCR is suitable for the measurement of proviral and viral load in experimental and clinical settings.

[Cytokine-producing lymphoma T cells in the skin and peripheral blood associated with atopy and hypereosinophilia]. / Kutane Zytokin-produzierende T-Lymphomzellen assoziiert mit Atopie und Hypereosinophilie.

A 47 year old female with a history of hay fever and a family history of atopic eczema developed localized pruritic eczematous lesions over a three year period. The lesions became generalized within just three months. Episodes of recurrent erythroderma followed and became resistant towards any therapy. Many immediate and some delayed hypersensitivity reactions were diagnosed. In the peripheral blood, leukocytosis and hypereosinophilia were observed. In addition, levels of total IgE were highly increased in serum. Immunophenotyping of the peripheral blood T cells revealed evidence for a clonal expansion of highly activated CD4(+) T cells with reduced CD2 and CD5 surface expression. After a three-year course of severe disease, the diagnosis of a pleomorphic T cell lymphoma of the small-cell variant was established by histological examination and a polymerase-chain reaction technique to determine the rearrangements of the gamma chain of the T cell receptor. Moreover, analysis of cytokine gene expression suggested that the high IgE concentrations and eosinophil numbers observed in this patient were likely due to an increased IL-5 and IL-13 production by lymphoma T cells.